OP0112 THE EVER-LARGEST ASIAN GWAS FOR SYSTEMIC SCLEROSIS AND TRANS-POPULATION META-ANALYSIS IDENTIFIED SEVEN NOVEL LOCI AND A CANDIDATE CAUSAL SNP IN A CIS-REGULATORY ELEMENT OF THE FCGR REGION
Authors: Y. Ishikawa, N. Tanaka, Y. Asano, M. Kodera, Y. Shirai, M. Akahoshi, M. Hasegawa, T. Matsushita, S. Kazuyoshi, S. Motegi, H. Yoshifuji, A. Yoshizaki, T. Kohmoto, K. Takagi, A. Oka, M. Kanda, Y. Tanaka, Y. Ito, K. Nakano, H. Kasamatsu, A. Utsunomiya, A. Sekiguchi, H. Niro, M. Jinnin, K. Makino, T. Makino, H. Ihn, M. Yamamoto, C. Suzuki, H. Takahashi, E. Nishida, A. Morita, T. Yamamoto, M. Fujimoto, Y. Kondo, D. Goto, T. Sumida, N. Ayuzawa, H. Yanagida, T. Horita, T. Atsumi, H. Endo, Y. Shima, A. Kumanogoh, J. Hirata, N. Otomo, H. Suetsugu, Y. Koike, K. Tomizuka, S. Yoshino, X. Liu, S. Ito, K. Hikino, A. Suzuki, Y. Momozawa, S. Ikegawa, Y. Tanaka, O. Ishikawa, K. Takehara, T. Torii, S. Sato, Y. Okada, T. Mimori, F. Matsuda, K. Matsuda, I. Imoto, K. Matsuo, M. Kuwana, Y. Kawaguchi, K. Ohmura, C. Terao
Journal: Annals of the Rheumatic Diseases (2022)

Background Genome-wide association studies (GWASs) have identified 29 disease-associated single nucleotide polymorphisms (SNPs) for systemic sclerosis (SSc) in non-human leukocyte antigen (HLA) regions (1-7). While these GWASs have clarified genetic architectures of SSc, study subjects were mainly Caucasians limiting application of the findings to Asians. Objectives The study was conducted to identify novel causal variants for SSc specific to Japanese subjects as well as those shared with European population. We also aimed to clarify mechanistic effects of the variants on pathogenesis of SSc. Methods A total of 114,108 subjects comprising 1,499 cases and 112,609 controls were enrolled in the two-staged study leading to the ever-largest Asian GWAS for SSc. After applying a strict quality control both for genotype and samples, imputation was conducted using the reference panel of the phase 3v5 1,000 genome project data combined with a high-depth whole-genome sequence data of 3,256 Japanese subjects. We conducted logistic regression analyses and also combined the Japanese GWAS results with those of Europeans (6) by an inverse-variance fixed-effect model. Polygenicity and enrichment of functional annotations were evaluated by linkage disequilibrium score regression (LDSC), Haploreg and IMPACT programs. We also constructed polygenic risk score (PRS) to predict SSc development. Results We identified three ( FCRLA-FCGR , TNFAIP3 , PLD4 ) and four ( EOMES , ESR1 , SLC12A5 , TPI1P2 ) novel loci in Japanese GWAS and a trans-population meta-analysis, respectively. One of Japanese novel risk SNPs, rs6697139, located within FCGR gene clusters had a strong effect size (OR 2.05, P=4.9×10 -11 ). We also found the complete LD variant, rs10917688, was positioned in cis-regulatory element and binding motif for an immunomodulatory transcription factor IRF8 in B cells, another genome-wide significant locus in our trans-ethnic meta-analysis and the previous European GWAS. Notably, the association of risk allele of rs10917688 was significant only in the presence of the risk allele of the IRF8 . Intriguingly, rs10917688 was annotated as one enhancer-related histone marks, H3K4me1, in B cells, implying that FCGR gene(s) in B cells may play an important role in the pathogenesis of SSc. Furhtermore, significant heritability enrichment of active histone marks and a transcription factor C-Myc were found in B cells both in European and Japanese populations by LDSC and IMPACT, highlighting a possibility of a shared disease mechanism where abnormal B-cell activation may be one of the key drivers for the disease development. Finally, PRS using effects sizes of European GWAS moderately fit in the development of Japanese SSc (AUC 0.593), paving a path to personalized medicine for SSc. Conclusion Our study identified seven novel susceptibility loci in SSc. Downstream analyses highlighted a novel disease mechanism of SSc where an interactive role of FCGR gene(s) and IRF8 may accelerate the disease development and B cells may play a key role on the pathogenesis of SSc. References [1]F. C. Arnett et al. Ann Rheum Dis , 2010. [2]T. R. Radstake et al. Nat Genet, 2010. [3]Y. Allanore et al. PLoS Genet, 2011. [4]O. Gorlova et al. PLoS Genet , 2011. [5]C. Terao et al. Ann Rheum Dis , 2017. [6]E. López-Isac et al. Nat Commun , 2019. [7]W. Pu et al. J Invest Dermatol , 2021. Disclosure of Interests None declared